The present invention relates to therapeutic liver-regenerating agents for liver transplants, containing valine as an active ingredient. It also relates to hepatocyte growth promoters for liver transplants.
Hepatic failure is a terminal picture of many liver diseases and is treated by liver transplantation, but a lack of donor organs is becoming a worldwide problem. Living donor partial liver transplantation is recognized as a measure for overcoming the lack of organs, and facilities for partial liver transplantation are increasing in the United States and European countries having advanced transplantation technology. However, partial liver transplantation cannot be considered a safe operation for adults representing the majority of transplantation patients because the resectable liver weight of donors is often less than the necessary liver weight for recipients. Thus, there is a demand for a means for safe and rapid liver regeneration for small grafts.
Conventional medical protocols for safe partial liver transplantation involve calculating the normal liver volume of the patient from the body surface area and examining and evaluating the percentage of the graft to be transplanted to the normal liver volume. Examination of the graft weight/normal liver volume ratio and postoperative hepatic function tests showed that the lower limit of the graft volume should be about 30% of the normal liver volume, and therefore, larger grafts are generally used for adult living donor partial liver transplantation (Hepatology, 21, 1317 (1995); Ann. Surg., 224, 544 (1996); Ann. Surg. 227, 269 (1998)).
Factors or drugs having a liver-regenerating effect have been known. Hepatocyte growth factor (HGF) is now under study and development as a potential drug for promoting liver regeneration. The liver-regenerating effect of HGF on liver transplants was recently reported (Transplantation, 68, 39 (1999)).
It was also reported that the so-called amino acid blend transfusion formulations have a liver-regenerating effect after hepatic resection (Kleinberger G, Deutsch E, eds. xe2x80x9cNew aspects of clinical nutrition. Baselxe2x80x9d, karger, 548-557 (1983); JPEN., 10, 17-20 (1986); Physiol Bohemoslov., 34, 359-366 (1985).
Japanese Laid-open Patent Publication No. 8-067628 describes a therapeutic liver-regenerating agent containing valine as an active ingredient. This document describes that valine has a liver-regenerating effect after partial liver resection.
However, until now it has not been known that valine has a liver-regenerating effect on liver transplants; nor has it been known that valine promotes hepatocyte growth of liver transplants or promotes improvement, recovery or normalization of hepatic functions of liver transplants.
An object of the present invention is to provide a drug that can promote liver regeneration or hepatocyte growth after liver transplantation such as partial liver transplantation. Another object of the present invention is to provide a drug that can safely promote liver regeneration or hepatocyte growth even for small grafts. Still another object of the present invention is to provide a drug that can safely promote rapid liver regeneration or hepatocyte growth after liver transplantation.
As a result of careful studies to achieve the above objects, the present inventors accomplished the present invention on the basis of the finding that remarkable liver regeneration is observed when valine is administered to rats having received partial liver transplantation.
Accordingly, the present invention provides a therapeutic liver-regenerating agent for a liver transplant, containing valine as an active ingredient. The present invention also provides a therapeutic liver-regenerating agent after liver transplantation, containing valine as an active ingredient.
The present invention also provides a hepatocyte growth promoter for a liver transplant, containing valine as an active ingredient.,
The present invention also provides said therapeutic liver-regenerating agent or hepatocyte growth promoter, which promotes improvement, recovery or normalization of hepatic functions of the liver transplant.
The present application claims priority based on Japanese Laid-open Patent Publication No. 11-235283, the disclosure of which is wholly incorporated herein as reference.
Valine used in the present invention may be commercially available or synthesized or prepared by any process. It may be in any of D-, L- and DL-configurations, but preferably L-configuration.
In the present invention, the term xe2x80x9cliver transplantationxe2x80x9d has the common meaning in the art and includes partial and whole liver transplantations in which the liver of a donor is partially or wholly resected and partially or wholly transplanted into a recipient. Partial liver transplantation is classified by operation mode into orthotopic partial liver transplantation, heterotopic partial liver transplantation and the like, and the present invention can be applied to any of them. In partial liver transplantation, a liver transplant or a partial liver transplant from a donor corresponding to about 30-50% of the normal liver volume of a recipient is typically transplanted as a graft into the recipient whose liver has been wholly resected, but the present invention has the effect of promoting liver regeneration or hepatocyte growth even if the graft is about 30% or less.
As used herein, xe2x80x9cliver transplantxe2x80x9d means a liver transplanted into a recipient by the transplantation operation as described above, and also includes the so-called xe2x80x9cpartial liver transplantxe2x80x9d corresponding to a graft consisting of a part of the liver of a donor.
As used herein, xe2x80x9cliver regenerationxe2x80x9d after liver transplantation means morphologic changes in which lost liver tissues are replaced by hepatocyte growth of a liver transplant or partial liver transplant, but also includes biochemical changes such as improvement, recovery or normalization of hepatic functions.
The preferred administration route is normally intravenous, but oral, enteral and the like administrations are also suitable. Valine used in the present invention can be applied alone as a formulation exclusively containing it, but preferably is combined with a transfusion formulation such as an intravenous hyperalimentation formulation containing glucose or the like or added to a transfusion formulation.
Suitable dosage forms include solutions, suspensions, emulsions, tablets, capsules, granules, fine granules, powders, suppositories, etc. These dosage forms are preferably prepared with pharmaceutically acceptable liquid or solid additives such as excipients, fillers, extenders, solvents, emulsifiers, lubricants, flavoring agents, perfumes, dyes, buffering agents, etc.
The dose depends on the sex, body type, constitution, age and condition of the patient and the dosage form used, but can be appropriately chosen at a valine level of 0.5-10.0%, preferably 0.5-5.0% in the case of transfusion formulations such as amino acid transfusion formulations to be administered from peripheral veins or central veins, or 0.5-10.0% in the case of ampules or vials to be added to transfusions, or 5.0-100% in the case of other dosage forms for oral or enteral administration such as suspensions, emulsions, tablets, capsules, granules, fine granules, powders, suppositories, etc.
Administration can be started at any time after liver transplantation. The administration period need not be long because a rapid liver-regenerating effect can be expected from the present invention, normally after administration for 5 days at a minimum, but preferably 7-10 days.
Specific subjects to be treated include, for example, patients who received partial liver transplantation after the liver had been wholly resected for treating hepatic failure caused by liver diseases such as hepatitis, hepatic cirrhosis of alcoholic, viral, drug or unknown cause or hepatic cancer.
As used herein, xe2x80x9c%xe2x80x9d representing valine levels means w/v % when valine is liquid or w/w % when valine is solid.